This study evaluates the performance of the Bruker positron emission tomograph (PET) insert combined with a BioSpec 70/30 USR magnetic resonance imaging (MRI) scanner using the manufacturer ...acceptance protocol and the NEMA NU 4-2008 for small animal PET. The PET insert is made of 3 rings of 8 monolithic LYSO crystals (50 × 50 × 10 mm3) coupled to silicon photomultipliers (SiPM) arrays, conferring an axial and transaxial FOV of 15 cm and 8 cm. The MRI performance was evaluated with and without the insert for the following radiofrequency noise, magnetic field homogeneity and image quality. For the PET performance, we extended the NEMA protocol featuring system sensitivity, count rates, spatial resolution and image quality to homogeneity and accuracy for quantification using several MRI sequences (RARE, FLASH, EPI and UTE). The PET insert does not show any adverse effect on the MRI performances. The MR field homogeneity is well preserved (Diameter Spherical Volume, for 20 mm of 1.98 ± 4.78 without and −0.96 ± 5.16 Hz with the PET insert). The PET insert has no major effect on the radiofrequency field. The signal-to-noise ratio measurements also do not show major differences. Image ghosting is well within the manufacturer specifications (<2.5%) and no RF noise is visible. Maximum sensitivity of the PET insert is 11.0% at the center of the FOV even with simultaneous acquisition of EPI and RARE. PET MLEM resolution is 0.87 mm (FWHM) at 5 mm off-center of the FOV and 0.97 mm at 25 mm radial offset. The peaks for true/noise equivalent count rates are 410/240 and 628/486 kcps for the rat and mouse phantoms, and are reached at 30.34/22.85 and 27.94/22.58 MBq. PET image quality is minimally altered by the different MRI sequences. The Bruker PET insert shows no adverse effect on the MRI performance and demonstrated a high sensitivity, sub-millimeter resolution and good image quality even during simultaneous MRI acquisition.
Background
Gallium-68 labeled synthetic somatostatin analogs for PET/CT imaging are the current gold standard for somatostatin receptor imaging in neuroendocrine tumor patients. Despite good imaging ...properties, their use in clinical practice is hampered by the low production levels of
68
Ga eluted from a
68
Ge/
68
Ga generator. In contrast,
18
F-tracers can be produced in large quantities allowing centralized production and distribution to distant PET centers.
18
FAlF-NOTA-octreotide is a promising tracer that combines a straightforward Al
18
F-based production procedure with excellent in vivo pharmacokinetics and specific tumor uptake, demonstrated in SSTR2 positive tumor mice. However, advancing towards clinical studies with
18
FAlF-NOTA-octreotide requires the development of an efficient automated GMP production process and additional preclinical studies are necessary to further evaluate the in vivo properties of
18
FAlF-NOTA-octreotide. In this study, we present the automated GMP production of
18
FAlF-NOTA-octreotide on the Trasis AllinOne® radio-synthesizer platform and quality control of the drug product in accordance with GMP. Further, radiometabolite studies were performed and the pharmacokinetics and biodistribution of
18
FAlF-NOTA-octreotide were assessed in healthy rats using μPET/MR.
Results
The production process of
18
FAlF-NOTA-octreotide has been validated by three validation production runs and the tracer was obtained with a final batch activity of 10.8 ± 1.3 GBq at end of synthesis with a radiochemical yield of 26.1 ± 3.6% (dc), high radiochemical purity and stability (96.3 ± 0.2% up to 6 h post synthesis) and an apparent molar activity of 160.5 ± 75.3 GBq/μmol. The total synthesis time was 40 ± 3 min. Further, the quality control was successfully implemented using validated analytical procedures. Finally,
18
FAlF-NOTA-octreotide showed high in vivo stability and favorable pharmacokinetics with high and specific accumulation in SSTR2-expressing organs in rats.
Conclusion
This robust and automated production process provides high batch activity of
18
FAlF-NOTA-octreotide allowing centralized production and shipment of the compound to remote PET centers. Further, the production process and quality control developed for
18
FAlF-NOTA-octreotide is easily implementable in a clinical setting and the tracer is a potential clinical alternative for somatostatin directed
68
Ga labeled peptides obviating the need for a
68
Ge/
68
Ga-generator. Finally, the favorable in vivo properties of
18
FAlF-NOTA-octreotide in rats, with high and specific accumulation in SSTR2 expressing organs, supports clinical translation.
Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations ...were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.
Background
Mesenchymal stem cells (MSCs) have shown potential for treatment of different diseases. However, their working mechanism is still unknown. To elucidate this, the non-invasive and ...longitudinal tracking of MSCs would be beneficial. Both iron oxide-based nanoparticles (Fe
3
O
4
NPs) for magnetic resonance imaging (MRI) and radiotracers for positron emission tomography (PET) have shown potential as in vivo cell imaging agents. However, they are limited by their negative contrast and lack of spatial information as well as short half-life, respectively. In this proof-of-principle study, we evaluated the potential of Fe
3
O
4
@Al(OH)
3
NPs as dual PET/MRI contrast agents, as they allow stable binding of
18
FF
−
ions to the NPs and thus, NP visualization and quantification with both imaging modalities.
Results
18
F-labeled Fe
3
O
4
@Al(OH)
3
NPs (radiolabeled NPs) or mouse MSCs (mMSCs) labeled with these radiolabeled NPs were intravenously injected in healthy C57Bl/6 mice, and their biodistribution was studied using simultaneous PET/MRI acquisition. While liver uptake of radiolabeled NPs was seen with both PET and MRI, mMSCs uptake in the lungs could only be observed with PET. Even some initial loss of fluoride label did not impair NPs/mMSCs visualization. Furthermore, no negative effects on blood cell populations were seen after injection of either the NPs or mMSCs, indicating good biocompatibility.
Conclusion
We present the application of novel
18
F-labeled Fe
3
O
4
@Al(OH)
3
NPs as safe cell tracking agents for simultaneous PET/MRI. Combining both modalities allows fast and easy NP and mMSC localization and quantification using PET at early time points, while MRI provides high-resolution, anatomic background information and long-term NP follow-up, hereby overcoming limitations of the individual imaging modalities.
Up to 40% of congenital diseases present disturbances of brain and craniofacial development resulting in simultaneous alterations of both systems. Currently, the best available method to ...preclinically visualize the brain and the bones simultaneously is to co-register micro-magnetic resonance (µMR) and micro-computed tomography (µCT) scans of the same specimen. However, this requires expertise and access to both imaging techniques, dedicated software and post-processing knowhow. To provide a more affordable, reliable and accessible alternative, recent research has focused on optimizing a contrast-enhanced µCT protocol using iodine as contrast agent that delivers brain and bone images from a single scan. However, the available methods still cannot provide the complete visualization of both the brain and whole craniofacial complex. In this study, we have established an optimized protocol to diffuse the contrast into the brain that allows visualizing the brain parenchyma and the complete craniofacial structure in a single ex vivo µCT scan (whiceCT). In addition, we have developed a new technique that allows visualizing the brain ventricles using a bilateral stereotactic injection of iodine-based contrast (viceCT). Finally, we have tested both techniques in a mouse model of Down syndrome, as it is a neurodevelopmental disorder with craniofacial, brain and ventricle defects. The combined use of viceCT and whiceCT provides a complete visualization of the brain and bones with intact craniofacial structure of an adult mouse ex vivo using a single imaging modality.
Stem cell tracking in cellular therapy and regenerative medicine is an urgent need, superparamagnetic iron oxide nanoparticles (IONPs) could be used as contrast agents in magnetic resonance imaging ...(MRI) that allows visualization of the implanted cells ensuring they reach the desired sites in vivo. Herein, we report the study of the interaction of 3,4-dihydroxyhydrocinnamic acid (DHCA) functionalized IONPs that have desirable properties for T
- weighted MRI, with bone marrow-derived primary human mesenchymal stem cells (hMSCs). Using the multiparametric high-content imaging method, we evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology and determine that the hMSCs are minimally affected after labelling with IONPs. Their cellular uptake is visualized by transmission electron microscopy (TEM) and Prussian Blue staining, and quantified using an iron specific colourimetric method. In vitro and in vivo studies demonstrate that these IONPs are biocompatible and can produce significant contrast enhancement in T
-weighted MRI. Iron oxide nanoparticles are detected in vivo as hypointense regions in the liver up to two weeks post injection using 9.4 T MRI. These DHCA functionalized IONPs are promising contrast agents for stem cell tracking by T
-weighted MRI as they are biocompatible and show no evidence of cytotoxic effects on hMSCs.
Preterm birth is the most significant problem in contemporary obstetrics accounting for 5-18% of worldwide deliveries. Encephalopathy of prematurity encompasses the multifaceted diffuse brain injury ...resulting from preterm birth. Current animal models exploring the underlying pathophysiology of encephalopathy of prematurity employ significant insults to generate gross central nervous system abnormalities. To date the exclusive effect of prematurity was only studied in a non-human primate model. Therefore, we aimed to develop a representative encephalopathy of prematurity small animal model only dependent on preterm birth. Time mated New-Zealand white rabbit does were either delivered on 28 (pre-term) or 31 (term) postconceptional days by caesarean section. Neonatal rabbits underwent neurobehavioral evaluation on 32 days post conception and then were transcardially perfuse fixed. Neuropathological assessments for neuron and oligodendrocyte quantification, astrogliosis, apoptosis and cellular proliferation were performed. Lastly, ex-vivo high-resolution Magnetic Resonance Imaging was used to calculate T1 volumetric and Diffusion Tensor Imaging derived fractional anisotropy and mean diffusivity. Preterm birth was associated with a motoric (posture instability, abnormal gait and decreased locomotion) and partial sensory (less pain responsiveness and failing righting reflex) deficits that coincided with global lower neuron densities, less oligodendrocyte precursors, increased apoptosis and less proliferation. These region-specific histological changes corresponded with Magnetic Resonance Diffusion Tensor Imaging differences. The most significant differences were seen in the hippocampus, caudate nucleus and thalamus of the preterm rabbits. In conclusion this model of preterm birth, in the absence of any other contributory events, resulted in measurable neurobehavioral deficits with associated brain structural and Magnetic Resonance Diffusion Tensor Imaging findings.
Early diagnosis of disease and follow-up of therapy is of vital importance for appropriate patient management since it allows rapid treatment, thereby reducing mortality and improving health and ...quality of life with lower expenditure for health care systems. New approaches include nanomedicine-based diagnosis combined with therapy. Nanoparticles (NPs), as contrast agents for in vivo diagnosis, have the advantage of combining several imaging agents that are visible using different modalities, thereby achieving high spatial resolution, high sensitivity, high specificity, morphological, and functional information. In this work, we present the development of aluminum hydroxide nanostructures embedded with polyacrylic acid (PAA) coated iron oxide superparamagnetic nanoparticles, Fe
O
@Al(OH)
, synthesized by a two-step co-precipitation and forced hydrolysis method, their physicochemical characterization and first biomedical studies as dual magnetic resonance imaging (MRI)/positron emission tomography (PET) contrast agents for cell imaging. The so-prepared NPs are size-controlled, with diameters below 250 nm, completely and homogeneously coated with an Al(OH)
phase over the magnetite cores, superparamagnetic with high saturation magnetization value (Ms = 63 emu/g-Fe
O
), and porous at the surface with a chemical affinity for fluoride ion adsorption. The suitability as MRI and PET contrast agents was tested showing high transversal relaxivity (r
) (83.6 mM
s
) and rapid uptake of
F-labeled fluoride ions as a PET tracer. The loading stability with
F-fluoride was tested in longitudinal experiments using water, buffer, and cell culture media. Even though the stability of the
F-label varied, it remained stable under all conditions. A first in vivo experiment indicates the suitability of Fe
O
@Al(OH)
nanoparticles as a dual contrast agent for sensitive short-term (PET) and high-resolution long-term imaging (MRI).
Alterations to the cerebral microcirculation have been recognized to play a crucial role in the development of neurodegenerative disorders. However, the exact role of the microvascular alterations in ...the pathophysiological mechanisms often remains poorly understood. The early detection of changes in microcirculation and cerebral blood flow (CBF) can be used to get a better understanding of underlying disease mechanisms. This could be an important step towards the development of new treatment approaches. Animal models allow for the study of the disease mechanism at several stages of development, before the onset of clinical symptoms, and the verification with invasive imaging techniques. Specifically, pre-clinical magnetic resonance imaging (MRI) is an important tool for the development and validation of MRI sequences under clinically relevant conditions. This article reviews MRI strategies providing indirect non-invasive measurements of microvascular changes in the rodent brain that can be used for early detection and characterization of neurodegenerative disorders. The perfusion MRI techniques: Dynamic Contrast Enhanced (DCE), Dynamic Susceptibility Contrast Enhanced (DSC) and Arterial Spin Labeling (ASL), will be discussed, followed by less established imaging strategies used to analyze the cerebral microcirculation: Intravoxel Incoherent Motion (IVIM), Vascular Space Occupancy (VASO), Steady-State Susceptibility Contrast (SSC), Vessel size imaging, SAGE-based DSC, Phase Contrast Flow (PC) Quantitative Susceptibility Mapping (QSM) and quantitative Blood-Oxygenation-Level-Dependent (qBOLD). We will emphasize the advantages and limitations of each strategy, in particular on applications for high-field MRI in the rodent’s brain.
As degenerative joint diseases such as osteoarthritis (OA) progress, the matrix constituents, particularly collagen fibrils and proteoglycans, become damaged, therefore deteriorating the tissue's ...mechanical properties. This study aims to further the understanding of the effect of degradation of the different cartilage constituents on the mechanical loading environment in early stage OA. To this end, intact, collagen- and proteoglycan-depleted cartilage plugs were cyclically loaded in axial compression using an experimental model simulating in vivo cartilage-on-cartilage contact conditions in a micro-MRI scanner. Depletion of collagen and proteoglycans was achieved through enzymatic degradation with collagenase and chondroitinase ABC, respectively. Using a displacement-encoded imaging sequence (DENSE), strains were computed and compared in intact and degraded samples. The results revealed that, while degradation with one or the other enzyme had little effect on the contact strains, degradation with a combination of both enzymes caused an increase in the means and variance of the transverse, axial and shear strains, particularly in the superficial zone of the cartilage. This effect indicates that the balance between cartilage matrix constituents plays an essential role in maintaining the mechanical properties of the tissue, and a disturbance in this balance leads to a decrease of the load bearing capacity associated with degenerative joint diseases such as OA.
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